Boron neutron capture therapy (BNCT) is a form of radiation therapy requiring two components: 10B and low energy thermal neutrons. The 10B is administered to the subject to be treated in the form of a boron-containing compound that accumulates in the tumour. The subject to be treated is then irradiated with low energy thermal neutrons from a nuclear reactor or cyclotron.
When low energy thermal neutrons hit 10B, they generate an α-particle and 7Li. The thermal neutrons have a relatively low energy. However, upon generation of 7Li and an α-particle, sufficient energy to destroy a cell is generated. Since the α-particle and 7Li are relatively large, they are only transported about 5-10 μm in the tissue, i.e. a distance corresponding to the diameter of a tumour cell. Thus, BNCT can be used to selectively irradiate tumours while minimizing the radiation damage to non-malignant tissue.
A major challenge in BNCT is to find a non-toxic carrier molecule for: the boron atom that will concentrate in the cells of the tumour to ensure sufficient selectivity. Such compounds should preferably deliver average 10B concentrations of 15-30 μg/g (ppm, i.e. parts per million) in tumours with high selectivity (tumour-to-blood and tumour-to-normal tissues ratios ideally>5) and with low toxicity, in order to attain a high therapeutic ratio. One approach has been to use boron-containing nucleosides, nucleotides or oligonucleotides (EP 1 113 020 A2). Another approach has been the use of nucleosides and oligonucleotides comprising a boronated phosphoramidate (WO 94/01440 A1). Further, carboranyl pyrimidines have been prepared for use in BNCT. Purine and pyrimidine nucleosides containing a carboranyl group attached to the purine or pyrimidine base have also been reported. The synthesis of nidocarborane-cobalamin conjugates that could be useful in neutron capture therapy has also been performed (H. P. C. Hogenkamp et al., Nuclear Medicine and Biology (2000), 27, 89-92).
Two boron neutron capture agents currently in phase I/II clinical trials are disodium mercapto-closo-dodecaborate (BSH) and 1-4-dihydroxyborylphenylalanine (BPA). Although BSH and BPA have been shown to be safe and efficacious in animal models, both of these agents have only moderate selectivity for tumour cells and low retention times in tumours. Furthermore, BSH has limited chemical stability due to its tendency toward air-oxidation, and BPA, although chemically non-toxic, contains only a low percent of boron by weight (5%) so that large amounts of this drug are needed in order to achieve therapeutic boron concentrations in tumour tissue.
Leamon, C. P. and Reddy, J. A., Advanced Drug Delivery Reviews, 56 (2004) 1127-1141, discusses the folate receptor and folate-drug conjugates for therapeutic purposes.
WO 00/45857 discloses the use of a physiologically compatible compound constituted by a Gd3+ complex moiety and a tumour specific moiety of biological or synthetic origin, for producing preparations for neutron capture and photon activation therapy.